This proposal describes a 5 year mentored training program to provide the applicant with intensive training in the areas of cytotoxic T cell responses and HIV viral pathogenesis and to advance the applicant's research skills and expertise to facilitate her development as an independent investigator. The candidate will be mentored by established investigators, Drs. Paul Goepfert and Jiri Mestecky, who are recognized leaders in immunology and vaccine development for HIV. She also has the support of a multidisciplinary advisory committee and will pursue a program of education through didactic coursework, conferences and seminars. She will engage in a research project examining the role of apoptosis in cytotoxic T lymphocyte (CTL) responses in HIV infection and how this contributes to the failure of the immune response to control HIV replication as well as factors regulating CTL survival. Despite a robust antigen-specific cytotoxic T lymphocyte (CTL) response early in infection, control of HIV replication fails in most patients. Understanding the components necessary in generating and maintaining an effective CTL response is imperative to developing effective therapeutic and preventative vaccines. We have previously focused on the quality of the response and have found that polyfunctional CTL responses, capable of cytokine secretion, proliferation and degranulation after antigen recognition, are generated in acute infection and maintained in LTNP (long term non-progressors). However, it is not certain what factors contribute to the maintenance of these polyfunctional CTL. HIV specific CDS T cells are preferentially primed for apoptosis but it is likely that some CTL are more resistant to apoptosis than others. CTL with higher levels of Bcl-2 are more resistant to apoptosis. BCL is in turn regulated by costimulatory signals such as 4-1BB and cytokines, including IL-15. Based on these observations we hypothesize that CTL derived from LTNP are maintained into chronic infection because they are relatively resistant to apoptosis. This project proposes to elucidate the pro-and anti-apoptotic factors contributing to survival of CTL in LTNP and determine the costimulatory signaling necessary to generate effective CTL capable of resisting apoptosis. The Departments of Medicine and Microbiology/Immunology at the University of Alabama provide an ideal setting for training physician scientist in translational research by combining state of the art research facilities, excellent career development resources, and a broad clinical base. In this environment, the candidate will have great opportunities to enrich her scientific experiences and develop her career path as an academician. Lay Statement- Understanding the effective immune response in HIV infected patients who control virus will help us design better therapeutic and preventative vaccines.